Back to EveryPatent.com
| United States Patent |
5,733,559
|
|
Citernesi
|
March 31, 1998
|
Controlled release inclusion system of glycolic acid in
.beta.-cyclo-dextrin and process for the above system preparation
Abstract
Glycolic acid controlled release inclusion complexes comprising glycolic
acid and .beta.-cyclodextrin.
| Inventors:
|
Citernesi; Ugo (Arcore, IT)
|
| Assignee:
|
I.R.A. Istituto Ricerche Applicate S.r.l. (Usmate-Velate, IT)
|
| Appl. No.:
|
659803 |
| Filed:
|
June 7, 1996 |
Foreign Application Priority Data
| Jun 09, 1995[IT] | MI95A1224 |
| Current U.S. Class: |
424/401; 424/450; 424/451 |
| Intern'l Class: |
A61K 007/00 |
| Field of Search: |
424/450,401,451
514/54
|
References Cited
U.S. Patent Documents
| 4767748 | Aug., 1988 | Ganguly | 514/54.
|
| 5575987 | Nov., 1996 | Kamei | 424/451.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Faulkner; D.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt, P.C.
Claims
I claim:
1. Glycolic acid controlled release inclusion complexes comprising glycolic
acid and .beta.-cyclodextrin.
2. Inclusion complexes according to claim 1 characterized in that glycolic
acid content is comprised between 10 to 50%.
3. Inclusion complexes according to claim 2 characterized in that the
glycolic acid content is 50%.
4. Cosmetic composition containing glycolic acid in form of a controlled
release inclusion complex with .beta.-cyclodextrin.
5. Cosmetic composition according to claim 4, characterized in that
glycolic acid concentration is comprised between 0.5 and 10%.
6. Process for the manufacture of glycolic acid/.beta.-cyclo-dextrin
inclusion complexes characterized in that glycolic acid is reacted with
.beta.-cyclo-dextrin.
7. Process according to claim 6, characterized in that glycolic acid is in
form of an aqueous solution and water is removed by evaporation to recover
the complex in anhydrous form.
8. Process according to claim 6, characterized in that glycolic acid is in
melted form and cyclodextrin is gradually added thereto.
9. Process according to claim 8, characterized in that the reaction takes
place at a temperature in range of 70.degree. to 120.degree. C.
Description
FIELD OF THE INVENTION
The present invention concerns glycolic acid controlled release inclusion
systems consisting of a complex between .beta.-cyclodextrin and glycolic
acid as active ingredient to be used in the dermatocosmetic and
dermatopharmaceutical fields. Some alpha-hydroxy-acids, among which the
more simple is glycolic acid, are present in the skin as natural products,
as they are commonly synthesized in the normal organism metabolism. Said
alpha-hydroxy-acids (shortly referred to as AHA) exhibit specific
functions within the horny layer of epidermis in that, besides having a
skin hydrating action, they act on the horny layer desquamation processes,
by controlling their correct development and avoiding any
hyperkeratinization.
As a matter of fact the appearance of a very dehydrated skin is
characterized by the thickening of the horny layer, known as
hyperkeratinization, which takes place as a consequence of the external
layer lower desquamation degree, due to a higher cohesion existing among
the corneocytes. Such process determinates the very characteristic
external appearance of the dry skin: rough to the touch, poorly elastic,
wrinkly in appearance.
There are many molecules controlling the desquamation level in the skin:
water, retinoids, alpha-hydroxy-acids, alpha-acetoxy-acids. Among them,
the first three promote the desquamation level, whilst
alpha-acetoxy-acids, being the alpha-hydroxy-acid natural antagonists,
tend to reduce the desquamation level. Desquamation process depends on the
bond strength established among corneocytes: a higher level of
intercorneocyte cohesion corresponds to a lower desquamation level and
vice versa.
SUMMARY OF THE INVENTION
It has been found that by topical administrating 2-5% alpha-hydroxy-acid
containing formulation products a horny layer exfoliating and regenerating
action is obtained, which is not immediate, but it is apparent after
two-three week treatment. Depending on alpha-hydroxy acid concentration,
different effects are obtained: at lower concentrations only the hydrating
and plasticizing effects are obtained whilst at higher concentrations the
separation-exfoliating effect takes place.
However it is also well known that glycolic acid, as well as other
alpha-hydroxy acids, has a skin irritating effect, therefore its high
concentration administration to reach the sought effects is very
problematic.
It is an object of the present invention a glycolic acid inclusion complex
that allows to enhance the active ingredient effectiveness while reducing
its irritating index.
It is a further object of the present invention a process for the
manufacture of the above inclusion complexes.
It is another object of the present invention the use of said inclusion
complexes for the cosmetic or dermato-therapeutic formulation.
These and other objects can be obtained according to the present invention
providing for the manufacture of glycolic acid/.beta. cyclo-dextrin
inclusion complexes.
Cyclo-dextrin are cyclic oligosaccharides deriving from starch degradation
by means of the cyclodextrin-glucosil-transferase an enzyme produced by
various microorganisms.
It has been found that by reacting glycolic acid with .beta.-cyclo-dextrin
inclusion complexes are formed which provide for a glycolic acid gradual
release.
Such glycolic acid controlled release not only increases its
bioavailability in time but being the free form glycolic acid only
gradually available its irritating action is reduced.
DETAILED DESCRIPTION OF THE INVENTION
The preparation of the inclusion complex may be accomplished by contacting
cyclodextrin and an aqueous solution of glycolic acid, and removing the
excess water. Preferably the inclusion complex is prepared by melting the
desired amount of glycolic acid then adding gradually the
.beta.-cyclodextrin under stirring and at such temperature to maintain the
mixture in liquid state.
The reaction temperature in such a case is advantageously comprised between
70.degree. C. and 120.degree. C. degrees. Preferably the temperature is
kept at 80.degree.-90.degree. C. The behaviour of the glycolic acid
present into the cyclodextrin complex has two effects: firstly glycolic
acid availability is prolonged in time and therefore its effectiveness is
remarkably increased, secondly glycolic acid is always present at low
concentration providing for a lower irritating effect of the product.
On the other hand cyclo-dextrins are pharmaceutical and cosmetic accepted
products and the complex formation with glycolic acid does not alter in
any way the glycolic acid dermatologic properties other then reducing its
irritating effect. The .beta.-cydodextrin/glycolic acid inclusion complex
may advantageously contain 10 to 50% of glycolic acid.
The inclusion complex according to the invention may be formulated in form
of cream, ointment, lotion a. s. o. and in addition it may contain
pharmaceutical and cosmetic acceptable eccipients.
Preferably the glycolic acid concentration in the cosmetic formulation may
range from 1.5 to 10%, in the dermatologic field the complex can be used
as such. The product has the appearance of a water soluble viscous liquid,
particularly able to be formulated with the conventional formulation
methods well known to the experts in the art.
The following examples illustrates preparation and use of
.beta.-cyclodextrin/glycolic acid inclusion complex with a 50% glycolic
acid concentration, but it are not intended to limit the scope of the
present invention.
Complex Preparation
EXAMPLE 1
70 g of glycolic acid in a 70% aqueous solution was mixed with 49 g powder
.beta.-cyclodextrin at room temperature. The mixture was subject to
energetic stirring to obtain a homogeneous viscous liquid. The above
product was heated to 70.degree.-80.degree. C. and kept under stirring at
said temperature up to a complete water evaporation. 98 g of a product was
obtained consisting of 50% glycolic acid.
EXAMPLE 2
50 g of glycolic acid was heated up to 80.degree. C. until melting of the
product in a round flask equipped with mechanical stirrer. Keeping the
melted product under vigorous stirring cyclodextrin (50 g) was added
thereto in a period of 30 minutes. The mixture was kept under stirring for
a period of 10 minutes, then it was gradually cooled down to room
temperature.
Thermal differential analysis of the product obtained under a) and b) shows
that a complex was obtained having a melting point different from the ones
of cyclodextrin and glycolic acid.
Assessment of the efficacy and of the cutaneous tolerability of the
.beta.-cyclodextrin complex of glycolic acid (CCAG) compared with free
glycolic acid (AG)
Test of cutaneous tolerability
Two series of tests were carried out to assess the index of cutaneous
irritation of free glycolic acid compared with the CCGA complex of
glycolic acid 50%, at various concentrations.
The first series of tests consisted in the test of cutaneous irritation or
epicutaneous test (Patch Test) by means of occlusive application.
For the second series of tests cutaneous irritation was determined
following non-occlusive applications.
Patch-test
Material
Free glycolic acid 70% (AG)--Du Pont
50% (CCAG)--prepared according the example 2 above
Samples
The samples of AG and of 50% CCAG were applied as water solution at
standard concentrations of 5% and 10%.
Selection of Volunteers
Ten healthy subjects were selected, of both sex, with negative anamnesis
for allergic dermatitis by contact (DAC) and without any other pathology
in process during the execution of the Test.
Material used for the Application of the Samples
The ready to use plasters for dermoreactions used for the Patch Test were
made of white "non woven fabric" with a dermatophilic mass of acrylic
adhesive, in the shape of 1 cm diameter disc, covered by small squares of
polyethylene.
Mode of Execution
The test was performed as follows: after cleansing with 70% alcoholic
solution (denatured ethyl alcohol the cutaneous area to be treated (volar
surfaces of the forearm), occlusive applications of the substance under
examination were carried out for one hour. After that period, the plasters
were removed and 15 minutes later the cutaneous reaction was evaluated and
classified on the basis of an arbitrary scale.
Cutaneous Reactions Considered
The cutaneous reactions considered were:
erythema
edema
exfoliation
vesiculation
Criteria of Assessment
According to the arbitrary scale used for the classification of the
cutaneous reactions, 0 corresponds to the absence of reaction, 1 point to
a light degree, 2 points to a moderate degree of reaction and 3 points to
a reaction of serious gravity.
Evaluation of the Results
For each volunteer scores were recorded for each parameter and the mean
value was calculated. The sum of four average values (one per parameter)
corresponds to the average index of cutaneous irritation (IIM).
Results
The products tested were classified on the basis of the average index of
cutaneous irritation (II M), reported in table 1.
TABLE 1
______________________________________
classification of the products tested on the basis of the correspondent
IIM.
Average index of cutaneous irritation
(IIM) Classification of the products
______________________________________
0,5 Non irritating
0,5-2 Slightly irritating
2-5 Moderately irritating
5-8 Very irritating
______________________________________
On the basis of the average of indices of cutaneous irritation obtained
both free (AG) and 50% CCGA resulted NON IRRITATING. However, the average
index of cutaneous irritation of free glycolic acid resulted, at
comparable concentrations, slightly higher compared to that of glycolic
acid complexed with cyclodextrins.
At 10% concentration, free glycolic acid resulted SLIGHTLY IRRITATING,
while the glycolic acid complex with cyclodextrins resulted NON
IRRITATING. At such concentration therefore AG showed an average index of
cutaneous irritation significantly and appreciably higher compared to that
of CCAG.
At the two concentrations tested, for both products, there was no evidence
of allergic reaction.
TABLE 2
______________________________________
average indices of cutaneous irritation (M) of the
products tested and their classification.
Products tested IIM Classification
______________________________________
AG (col 5%) 0,2 Non irritating
CCAG (sol. 5%) 0,1 Non irritating
AG (sol. 10%) 0,6 Slightly irritating
CCAG (sol. 10%) 0,1 Non irritating
______________________________________
Non occlusive application
Material
Free glycolic acid 70% (AG)--Du Pont
50% (CCAG)--prepared according to example 2
Preparation of the Samples
The samples of AG 50% CCAG were applied directly on the skin at 50%
concentration, pH 2,5 (in NH.sub.4 OH).
Selection of Volunteers
Eight healthy volumary women were chosen, aged between 30 and 50 (average
age 37,5).
Mode of Execution
The samples were applied on one half of the face (periocular and zygomatic
zone) using a badger brush. The duration of the application was decided
according to the type of skin and to the cutaneous reaction of the
individual volunteer. 5 applications were carried out, one every three or
more days according to the subjects.
The irritating effect was assessed before the application and one hour
after the application.
Cutaneous Reactions Considered
The parameters considered to clinically evaluate the irritating degree of
the substance under examination were the following:
no irritative reaction
irritative symptoms: erythema, pruritus, burning, desquamation, blistering,
eczematous reaction.
Criteria of Assessment
The irritating effect was assessed on the basis of an arbitrary scale,
based on clinical experience, recorded as follows:
0=No irritative reaction
1=Modest reaction (slight reddening, pruritus)
2=Irritative reaction (erythema, pruritus, desquamation)
3=Strong irritative reaction (erythema, burning, strong pruritus,
desquamation, and more)
Evaluation of the Results
After every application the cutaneous reactions of each volunteer were
evaluated and a relative score was given.
Results
There were no cases of irritation or sensitivity noted in any of the 8
subjects on the left side periocular and zygomatic areas of skin treated
with 50% CCAG.
On the right side periocular and zygomatic area of skin treated with free
glycolic acid (AG) 2 cases of irritation of average gravity were found
after the third application, resolved with the use of topical moisturizer
and reduction in the time of application, and one case of average to
serious irritation after the second application which required the
suspension of the treatment with AG (but not with CCAG on the cutis area
of the left side of the face) and the use of topical steroids. No subject
tolerated the product for more than three minutes.
TABLE 3
__________________________________________________________________________
Tolerability test of free glycolic acid (AG) and of its
complex with cyclodextrins (CCAG) on 8 volunteer subjects
RIGHT SIDE OF FACE
LEFT SIDE OF FACE
(AG) (CCAG)
no applications
1a 2a 3a 4a 5a 1a 2a 3a 4a 5a
applic. time (min)
1 min
2 min
3 min
3 min
3 min
1 min
2 min
3 min
4 min
5 min
__________________________________________________________________________
SUBJECT 1
0 2/3*
// // // 0 0 0 0 0
SUBJECT 2
0 0 2 0 0 0 0 0 0 0
SUBJECT 3
0 0 2 0 0 0 0 0 0 0
SUBJECT 4
0 0 0 0 0 0 0 0 0 0
SUBJECT 5
0 0 0 0 0 0 0 0 0 0
SUBJECT 6
0 0 0 0 0 0 0 0 0 0
SUBJECT 7
0 0 0 0 0 0 0 0 0 0
SUBJECT 8
0 0 0 0 0 0 0 0 0 0
__________________________________________________________________________
*Subject 1 had to suspend treatment at the second application because of
average to serious irritation.
As is seen in table 3, AG and CCAG had different effects on the subjects
tested. All the subjects tolerated CCAG even for 5 minute applications,
while the same subjects did not tolerate AG for more than 3 minutes. Also
CCAG did not cause any irritation whatsoever, while for AG there were 3
cases of irritation of grade 2 and 2/3.
Top